In HIV-endemic settings, many HIV-uninfected women choose to conceive with an HIV-infected or unknown- serostatus partner. For a woman who cannot depend on a partner to test, initiate and adhere to ART, sex without condoms puts her at high risk of acquiring HIV and increases the risk of perinatal transmission to her child. Daily, oral TDF/FTC PrEP dramatically reduces a woman's risk of HIV-acquisition and is the only female-controlled option for reducing her risk of periconception HIV-acquisition. Understanding whether daily, oral PrEP is feasible for uninfected women seeking pregnancy is critical to reducing HIV incidence among women and their children. We propose a single-arm study to offer daily, oral PrEP for periconception use to 350 HIV-uninfected women in KwaZulu-Natal, South Africa who report personal or partner plans for pregnancy with an infected or unknown serostatus partner. Women who become pregnant on PrEP will have the option to continue PrEP during pregnancy. PrEP will be offered as part of a safer conception package inclusive of couples-based HIV counseling and testing. In Aim 1, we will evaluate the proportion of women initiating PrEP and determine factors associated with uptake. In Aim 2, we will evaluate objectively-measured PrEP adherence during periconception and pregnancy follow-up. Level, patterns, and correlates of adherence will be evaluated using plasma drug concentrations and electronic pill caps. Our primary outcome is prevalence of protective plasma tenofovir concentrations (> 40 ng/ml). We will also evaluate median adherence to dispensed pills with electronic pill caps. From formative studies in South Africa, we hypothesize that adherence to a proven intervention (TDF/FTC PrEP) for a defined risk period (periconception, pregnancy) with a clear end point (live birth) will be high (protective tenofovir concentrations at 80% of visits, adherence to >80% of prescribed pills). In Aim 3, longitudinal quantitative data and in-depth interviews with initially high- and low-adhering participants will inform our conceptual framework for periconception PrEP uptake and adherence. Placebo-controlled trials identified adherence as a major challenge to long-term PrEP use. However, women are eager for prevention strategies that allow for conception, and we hypothesize that adherence to a proven prevention strategy, for a limited time with the motivation to have a healthy child, will confer drug levels required to prevent HIV transmission. Consistent with PA11-275 Discovery, Development, & Testing of Novel Interventions to Advance HIV Prevention and Care, this application advances combination approaches to HIV- prevention and targets a population highly affected by the pandemic. This project will determine whether daily, oral PrEP is a feasible HIV-prevention strategy for South African women who conceive with risky partners. Given the repercussions of acquiring HIV during conception and pregnancy, this is an important step towards providing a key prevention strategy to women and their children.